Objective To analyze the Podoplanin expression in patients with esophageal squamous cell carcinoma and to find out the relationship between Podoplanin expression and tumor embolus, lymph node metastasis, tumor differentiation as well as prognosis, and to provide clinical evidence for reducing the recurrence of esophageal squamous cell carcinoma and prolonging the disease-free survival and overall survival. Methods A retrospective analysis of 70 patients with esophageal squamous cell carcinoma in our hospital from June 2010 to June 2012 was conducted, including 39 males and 31 females, with a mean age of 63.6 years. Positive diagnosis of tumor thrombus was achieved in 35 patients and negative in 35 patients. Postoperative pathological specimens were examined and normal esophageal tissues (esophageal tissue more than 5 cm from the edge of the tumor) of patients were excised as a control group. Results The positive rate of Podoplanin was 34.2% in normal esophageal tissues and 62.8% in tumor tissues. The positive rate of Podoplanin expression was 77.1% and 48.6% in esophageal squamous cell carcinoma patients with or without tumor embolus, respectively. The positive rate of Podoplanin expression in tumor cells of patients with positive and negative lymph node metastasis was 71.9% and 23.1%, respectively (P<0.05). The mean disease-free survival of patients with Podoplanin expression-negative esophageal squamous cell carcinoma was 15.2 months, which was significantly longer than that of patients with Podoplanin expression-positive esophageal squamous cell carcinoma (P<0.05). Conclusion Podoplanin expression in the tumor cells and vessels can be an important reference index to the prognosis of patients with esophageal squamous cell carcinoma.